Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer's disease

Abstract

Although N-truncated Aβ variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer's disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer's disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Aβ peptides based on mounting evidence that they may represent better targets than full-length Aβ. In addition to Aβ peptides starting with an Asp at position 1, a variety of different N-truncated Aβ peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Aβ, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Aβs dominate full-length Aβ in the brains of Alzheimer's patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides.

Fig. 1

Sequence of the first 17 amino acids of the N-terminus of human Aβ is shown in three-letter and one-letter-code. Amino acids (AA) with charged polar side-chains are shown in red, AA with uncharged polar side-chains in green and hydrophobic non-polar AA in blue. The cleavage sites of enzymes involved in the degradation of full-length and potential generation of N-truncated Aβ peptides are indicated

Fig. 2

Comparative immunostaining against intact N-terminus and most prevalent N-truncated Aβ peptides Aβ_pE3–X, Aβ_4–X and Aβ_5–X in the brain of patients with sporadic Alzheimer’s disease. Staining was performed with antibodies 4G8 (a epitope Aβ_17–24), IC16 (b against Aβ_1–x; gift by Sascha Weggen [39]), 2–48 (c against Aβ_pE3–X; Synaptic Systems [107]), 9D5 (d against oligomeric Aβ_pE3–X; Synaptic Systems [108]), NT4X-167 (e against oligomeric Aβ_4–X; [3]) and AB5-3 (f against Aβ_5–X; PSL Heidelberg [29]). Scale bar 100 μm

Fig. 3

N-truncated pyroglutamate Aβ_3–42 and Aβ_4–42 are more toxic as compared to full-length Aβ_1–42 due to reduced neutralization via plaque formation. Upper graph Monomers and low- and high-molecular weight aggregates of Aβ_1–42 (blue) are in equilibrium and are toxic as long as they stay soluble [7]. Once high-molecular weight aggregates are formed, they rapidly react into highly ordered and insoluble, non-toxic fibrils found in plaques. Therefore, soluble low- and high-molecular weight oligomers are toxic, but can escape toxicity by forming monomers and/or fibrils. As Aβ_1–42 is a physiological peptide, which is continuously generated also in healthy individuals, plaque formation may be one way to neutralize full-length Aβ during the prodromal stage of the disease. Lower graph Soluble monomers, low- and high-molecular weight aggregates of N-truncated pyroglutamate Aβ_3–42 and Aβ_4–42 (red) are in disequilibrium and are toxic [7]. High-molecular weight aggregates also can be neutralized by plaque formation, but with a significant slower tendency as compared to full-length Aβ, because the fibrillization process is unordered forming only amorphous fibrils. As a consequence, the level of soluble low- and high-molecular weight aggregates of N-truncated Aβ variants increase over time, thereby playing a major role in AD pathology